Novel pregnanoic acid derivatives

ABSTRACT

CH=),8-X-PERHYDROBENZ(E)INDENE   PREGNANOIC ACID DERIVATIVES OF THE FORMULA   2-R1,3-(R3O-CO-CH(-OR2)-),3A,6-DI(H3C-),5-Z,6,7-(-B-A-CO- WHEREIN THE GROUP OR2 IS IN THE AF- OR BF-POSITION; X IS HYDROGEN, HALOGEN OR METHYL; Y IS HYDROGEN OR HALOGEN; Z IS HYDROXY OR HALOGEN HAVING AN ATOMIC WEIGHT NO GREATER THAN Y; R1 IS HYDROGEN OR METHYL; R2 IS HYDROGEN OR ACYL AND R3 IS HYDROGEN, ALKALI METAL OR SATURATED OR UNSATURATED UNSUBSTITUTED OR SUBSTITUTED HYDROCARBON OF 1-18 CARBON ATOMS, OR COLLECTIVELY R2 AND R3 ARE DIALKYLMETHYLENE OR CYCLOALKYLIDENE; AND AT LEAST ONE OF X, Y AND R1 ARE OTHER THAN HYDROGEN; AND -A-B- IS   -CH2-CH2-, -CH=CH- OR -CCL=CH;   POSSESS PRONOUNCED TOPICAL ANTI-INFLAMMATORY ACTIVITY AS WELL AS BEING INTERMEDIATES FOR THE PRODUCTION OF THE CORRESPONDING 20-KETO STEROIDS.

United States Patent 3,833,563 NOVEL PREGNANOIC ACID DERIVATIVES HenryLaurent, Rudolf Wiechert, Klaus Prezewowsky, Helmut Hofmeister, ErichGerhards, Klaus Mengel, and Karl Heinz Kolb, Berlin, Germany, assignorsto Schering Aktiengesellschaft, Berlin and Bergkamen, Germany NoDrawing. Continuation-impart of application Ser. No. 284,710, Aug. 30,1972. This application Oct. 3, 1972, Ser. No. 294,527 Claims priority,application Germany, Oct. 4, 1971, P 21 50 270.5; Feb. 22, 1972, P 22 09298.4, P22 09 312.5

Int. Cl. C07c 173/00 US. Cl. 260-23955 D 73 Claims ABSTRACT OF THEDISCLOSURE Pregnanoic acid derivatives of the formula wherein the group0R is in the LXF- or fi -position; X is hydrogen, halogen or methyl; Yis hydrogen or halogen; Z is hydroxy or halogen having an atomic weightno greater than Y; R is hydrogen or methyl; R is hydrogen or acyl and Ris hydrogen, alkali metal or saturated or unsaturated unsubstituted orsubstituted hydrocarbon of 118 carbon atoms, or collectively R and R aredialkylmethylene or cycloalkylidene; and at least one of X, Y and R areother than hydrogen; and AB is possess pronounced topicalanti-inflammatory activity as well as being intermediates for theproduction of the corresponding 20-keto steroids.

BACKGROUND OF THE INVENTION This invention relates to novel pregnanoicacid derivatives.

One of us, with others, has published the isolation of 6a.fluoro-l1B-01-3,20-dioXo-16a-methyl-pregna-1,4-dien- 21-acid (CompoundI) as a water-soluble metabolite of fluocortolone in humans. E. Gerhardset al., Acta Endrocrinologica, 68 (1971) 98-126. The preparation of theethyl ester thereof for characterization purposes was also reported inthat publication.

We have found that 21-oxy compounds useful for the production of theseand structurally related compounds claimed in the copending applicationof Laurent et al., SN 284,710, filed August 30, 1972, of which thisapplication is a continuation-in-part, possess valuable pharmacologicalactivity.

SUMMARY OF THE INVENTION COOR:

C OR:

wherein the group OR; is in the a or p -position; X is hydrogen, halogenor methyl; Y is hydrogen or halogen; Z is hydroxy or halogen having anatomic weight no greater than Y; R is hydrogen or methyl; R is hydrogenor acyl as defined hereinafter and R is hydrogen, an alkali-metal, or asaturated hydrocarbon of 1-18 carbon atoms which is unsubstituted orsubstituted, or a corresponding unsaturated hydrocarbon, or collectivelyR and R are dialkylmethylene or cycloalkylidene, at least one of R R andR is other than a hydrogen atom; and AB is CH CH CH=CH, CCl= CH--.

In another aspect, this invention relates to pharmaceuticalcompositions, especially pharmaceutical compositions adapted for topicalapplication, comprising one or more of the novel compounds of thisinvention.

In a further aspect, this invention relates to novel processes for theproduction of these compounds.

In a method of use aspect, this invention relates to the treatmenttopically of inflammatory conditions.

DETAILED DISCUSSION Of the compounds of Formula I, preferred sub-classesare those wherein:

Ia. R is alkyl of 112 carbon atoms, preferably 1-8 carbon atoms;

Ib. X and/or Z are chloro or fluoro, preferably fluoro, especially thoseof la;

Ic. Y is hydrogen, especially those of la and Ib;

Id. Z is hydroxy, especially those of Ia, *Ib and I0;

Ie. A--B is CH=CH, especially those of la, Ib, lo and Id;

If. R is methyl, especially those of Ia, Ib, Ic, Id and le;

Ig. R is sodium or potassium when R is alkali-metal, or alkyl of 1-4carbon atoms when R is alkyl; and

Ih. Y and Z are both chloro or Y is fluoro and Z is hydroxy.

Because activity resides in the pregnanoic acid steroidal structure,esters of the free 20-hydroxy group also possess the utility of the freealcohol.

Suitable 20-ester groups are those wherein R is the radical ofphysiologically acceptable acids. Examples of such acids are organiccarboXylic acids of up to 15 carbon atoms, preferably 1 to 12, morepreferably 1 to 8 carbon atoms. Although esters of alkanoic acids arepreferred, also suitable are esters of cycloaliphatic, carbocyclic aryl,aralkyl, alkaryl and heterocyclic carbocyclic acids. Examples of suchacids are formic acid, acetic acid, propionic acid, butyric acid,valeric acid, caproic acid, enanthic acid, uudecylic acid,trimethylacetic acid, diethylacetic acid, tert.-butylacetic acid,phenylacetic acid, cyclopentylpropionic acid, oleic acid, lactic acid,mono-, di-, and trichloroacetic acid, aminoacetic acid, diethylamino-,piperidino-, and morpholinoacetic acid, succinic acid, adipic acid,benzoic acid and nicotinic acid.

Especally preferred R acyl groups are alkanoyl of 1-8 carbon atoms andbenzoyl. However, R can be the acyl 3 radical of an acid which isunsaturated, branched, polybasic or substituted in the usual manner,e.g., by hydroxy, oxo or amino groups, or by halogen atoms.

Because activity resides in the pregnanoic acid steroidal structure,2l-carboxylic acid esters also posses the utility of the free21-carboxylic acid and its salts. Thus, COOR can also represent an estergroup. a

For example, R can be any hydrocarbon group of 1-18, preferably 1-12,carbon atoms. The hydrocarbon group can be, e.g., alkyl or cycloalkyl,preferably monocyclic, or carbocyclic aryl, aralkyl or alkaryl.

Examples of alkyl R groups are alkyl of 1-12, preferably 1-8, morepreferably l-4 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl,n-butyl and tert.-butyl. Examples of cycloalkyl R groups are thosecontaining 3-12, preferably 5 or 6 ring carbon atoms, e.g., cyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl and 1,4-methyleno-cyclohexyl andp-dicyclohexyl. Examples of carbocyclic aryl R groups are mono anddicyclic carbocyclic of up to 12 carbon atoms, e.g., phenyl, a-naphthyland fi-naphthyl and p-diphenyl. Examples of carbocyclic alkaryl R groupsare tolyl, xylyl, ethylphenyl and sym-diethylphenyl. Examples ofcarbocyclic aralykyl R groups are benzyl, phenethyl, a-phenpropyl anddiphenylmethyl.

Equivalents of the alkyl, cycloalkyl, carbocyclic aryl, aralkyl andalkaryl hydrocarbon are unsaturated alkyl and cycloalkyl. Examples ofunsaturated aliphatic are vinyl, allyl, propenyl, propynyl, butenyl andbutynyl. Examples of unsaturated cycloalkyl are cyclopentenyl andcyclopentadienyl.

Additional equivalents of hydrocarbon as defined above are hydrocarbongroups, preferably alkyl or phenyl, bearing 1, 2, 3 or more simplesubstituents, preferably one, since such substitutents preferably one,since such substituents ordinarily do not affect the overall activity ofthe parent pregnanoic acid. Examples of such simple substitutents arehydroxy, halo, e.g., C1 or F, N sulfato and alkali-metal salts thereof,amido, lower-alkoxy, i.e., containing 1-4 carbon atoms, e.g., methoxy,ethoxy, propoxy, butoxy and tert.-butoxy group; carboxy, thealkali-metal, e.g., sodium and potassium salts thereof and lower-alkylesters thereof, e.g., carbomethoxy. carboethoxy; amino groups and thepharmaceutically acceptable acid addition salts thereof, e.g., primaryamino, monoand di-lower-alkylamino, e.g., methylamino, dimethylamino,ethylamino, diethylamino, methyl, ethylamino, propylamino, butylaminoand the pharmaceutically acceptable acid addition salts thereof. Theacid addition salts are preferably those of the strong mineral acids,e.g., hydrochlorides, hydrobromides, sulfates and phosphates. and thepolybasic or hydroxy acids, e.g., oxalates, maleates, citrates andtartrates and any other pharmaceutically acceptable acid.

Examples of preferred R groups are methyl, carboxymethyl, ethyl,2-hydroxyethyl, 2-methoxyethyl, 2- aminoethyl, Z-dimethylaminoethyl,2-carboxyethyl, propyl, allyl, cyclopropyl, isopropyl, S-hydroxypropyl,propynyl, S-aminopropyl, butyl, sec.-butyl, tert.-butyl. 2- butyl,pentyl, isopentyl, tert.-pentyl, Z-methylbutyl, cyclopentyl, hexyl,cyclohexyl, cyclohex-Z-enyl, cyclopentylmethyl, heptyl, benzyl,2-phenylethyl, .octyl, bornyl, isobornyl, menthyl, nonyl, decyl,3-phenylpropyl, 3- phenylprop-Z-enyl, dodecyl, tetradecyl, hexadecyl andoctadecyl.

When R and R collectively are dialkylmethylene, the alkyl groups thereofare of 1-4 carbon atoms, i.e., the dialkylmethylene group contains up to9 carbon atoms. Examples are 2,2-propylidene, 2.2-butylidene,2,2-pentylidene, 3,3-pentylidene and 2,2-hexylidene. When R and R arecycloalkylidene, the cycloalkylidene is of to 7 ring carbon atoms andcontains up to a total of carbon atoms, preferably cyclopentylidene orcyclohexylidene.

In addition to the 16a-methyl compounds of the examples hereinafter,examples of 16 unsubstituted compounds of this invention are methylester of 60c-flu0rO11[3,20u

(a) reacting a 21-hydroxy steroid of the general Formula wherein -AB-,X, Y, Z and R have the values given above, with an alcohol in thepresence of a copper (II) salt; or

(b) rearranging a compound of the general Formula III III wherein -AB-.X, Y, Z and R have the values given above, and Q is one of thegroupings:

wherein R is an alkyl group and R is an acyl group, by treatment withstrong bases; and optionally thereafter, saponifying any ester groups ofthe thus-produced product, and/or esterifying a free ZO-hydroxy groupand/ or condensing a 21-oic acid with a ketone.

In the process of this invention according to method (a), preferredcopper (II) salts are salts of lower carboxylic acids, e.g., copper (II) formate, copper (II) acetate, copper (II) propionate, or copper (II)isobutyrate. Copper (II) salts of inorganic acids can also be utilized.

In the process of method (a), the alcohols which are employed as thereactants can also be used simultaneously as the reaction solvent. Itis, of course, also possible to employ other solvents which solvents areinert to the respective reaction conditions in addition to the alcohols.Examples of such solvents are hydrocarbons, e.g., benzene and toluene,and others, e.g., diethyl ether. di isopropyl ether, tetrahydrofuran anddioxane.

The reaction is preferably conducted at a reaction temperature of fromC. to 150 C. By conducting the process of this invention for at leasttwo days at room temperature, or at least two hours at the boiling temperature of the solvent or solvent mixture employed, the compounds ofgeneral Formula II are obtained directly from the compounds of generalFormula H.

In this preferred embodiment of the process of this invention, a rathercomplex succession of reactions takes place from the viewpoint ofreaction mechanisms. In spite of the complex course of the reaction,surprisingly, it is generally usable for the synthesis of esters ofgeneral Formula I wherein R is a primary, secondary, or tertiary estergroup.

By conducting the process of method (a) for -120 minutes at roomtemperature, one obtains, in addition to the compounds of generalFormula I, intermediates thereto of general Formula HIa wherein A--B, X,Y, Z, R and R have the values given above.

The compounds of general Formula IIIa can be converted to the compoundsof general Formula I not only according to method (a), but alsoaccording to method (b).

According to method (b), compounds of general Formula III are rearrangedinto the carboxylic acids of general Formula I by treatment with astrong base in an aqueous-alcoholic solution. Suitable strong bases arealkali hydroxides, such as, for example, sodium hydroxide, and potassiumhydroxide, alkaline earth hydroxides, e.g., calcium hydroxide and bariumhydroxide, quaternary ammonium bases, e.g., tetramethylammoniumhydroxide. This reaction can be conducted, for example, at roomtemperature or at an elevated temperature.

In the process of the invention, mixtures of the and 20fl -hydroxycompounds of general Formula I are produced. The respective isomers canbe separated from this mixture by chromatography and/or crystallization.

The saponification of the 21-esters of Formula I which optionally isconducted subsequently, can be conducted in accordance with conventionalmethods, e.g., by saponification of the esters in water or in aqueousalcohol, in the presence of acidic catalysts, e.g., hydrochloric acid,sulfuric acid or p-toluene-sulfonic acid, or in the presence of a basiccatalyst, e.g., potassium bicarbonate, potassium carbonate, sodiumhydroxide or potassium hydroxide.

The esterification of the free acids which also can optionally follow islikewise effected according to conventional reaction procedures. Thus,the free acids can be reacted, for example, with diazomethane ordiazoethane, thus obtaining the corresponding methyl and ethyl esters,respectively. A generally applicable method is the reaction of the acidswith the alcohols in the presence of carbonyl diimidazole, dicyclohexylcarbodimide or trifluoroacetic anhydride. It is also possible to convertthe acids into the silver salts thereof followed by reaction with analkyl halide.

Another method resides in converting free acids of Formula I into theircorresponding alkyl esters by reaction with a dimethylformamide alkylacetal. The acids can also be reacted with the alcohols or theloweralkanecarboxylic acid esters of the alcohols in the presence of astrongly acidic catalyst, e.g., hydrogen chloride, sulfuric acid,perchloric acid, trifluoromethylsulfonic acid or p-toluenesulfonic acid.It is also possible to convert the carboxylic acids into their acidchloride or acid anhydride which is then reacted with an alcohol in thepresence of a basic catalyst. The acid esters can also betransesterified in a conventional manner with an alcohol in the presenceof an acidic or basic catalyst.

The optional esterification of the 20-hydroxy steroids of generalFormula I is likewise conducted according to conventional methods. Thus,the 20-hydroxy steroids can be esterified, for example, with acarboxylic acid in the presence of carbonyl diimidazole, dicyclohexylcarbodiimide or trifluoroacetic anhydride, or with the correspondingacid anhydrides or acid chlorides in the presence of a basic catalyst,e.g., potassium bicarbonate, pyridine, lutidine or collidine.

The optionally condensation of the ZO-hydroxy-Zl-oic acids of generalFormula I with a ketone takes place in accordance with conventonaloperating methods, e.g., by reaction with an excess of the ketone in thepresence of a strongly acidic catalyst. In this reaction, the ketonereactant also can serve as the reaction solvent. Additional inertsolvents, e.g., dioxane, tetrahydrofuran and glycol dimethyl ether, canalso be employed.

Examples of ketones which can be used in the present process are, inparticular: dialkyl ketones, e.g., acetone, methyl ethyl ketone, diethylketone, methyl butyl ketone, ethyl butyl ketone, dipropyl ketone andcycloalkanones, e.g., cyclopentanone or cyclohexanone.

Preferred acidic catalyst for the condensation are mineral acids andLewis acids, e.g., hydrochloric acid, sulfuric acid, perchloric andboron trifiuoride.

This condensation can be effected at room temperature or at an elevatedtemperature of up to about 150 C.

The compounds of general Formula I, upon local application, exhibit ananti-inflammatory effectiveness which, in many cases, is greater thanthe anti-inflammatory effectiveness of the corresponding 21-hydroxysteroids and 2l-acyloxy steroids.

Topical anti-inflammatory effectiveness can be determined on the rat earin accordance with the method of Tonelli, as follows:

The substance to be tested is dissolved in an irritant, consisting of 4parts of pyridine, 1 part of distilled water, 5 parts of ether and 10parts of a 4% ethereal croton oil solution. Felt strips attached to theinsides of an object-slide pincette are saturated with this testsolution and the pincette is brought into contact, under slight pressurefor 15 seconds, with the right ear of male rats having a weight of -160g. The left ear remains untreated and serves as control. Three hoursafter the application, the animals are sacrificed and discs of 9 mm.diameter are punched from their ears. The weight difference between theslice of the right ear and that of the left ear is a measure for thethus-formed edema.

The dosage of test compound is determined at which no edema formationoccurs. From this dosage, the relative effectiveness of the testcompound, compared to the erectiveness of6a-fiuoro-l1fl,2l-dihydr0xy-l6zx-methyl-l, 4-pregnadiene-3,20-dione(:fluocortolone), is determined. Table I gives the results of suchtesting.

TABLE I.-RAT EAR TEST Relative efiectiveness as0x0-16a-methyl-l,4-pregnadien-21-oic acid.

Similar results are obtained when determining the local antiphlogisticeffectiveness according to the standard vaso-constriction test onhumans.

In addition to anti-inflammatory activity, the compounds of generalFormula I have a surprising spectrum of pharmacological properties. Forexample, the tested compounds were entirely inactive systemically, asevidenced by the pharmacological investigations:

SP'F rats (130l50 g.) are injected, for the generation of a focus ofinflammation with 0.1 ml. of a 0.5% Mycobacterium butyricum suspension(obtainable from the US. firm Difco) into the right hind paw. Prior tothe injection, the paw volume of the rats is measured. The paw volume isonce again measured 24 hours after injection to determine the extent ofthe edema. Thereafter, the rats receive subcutaneous injections ofvarying amounts of test substance dissolved in a mixture of 29% benzylbenzoate and 71% castor oil. After another 24 hours, paw volume is oncemore determined. The control animals are treated in the same manner,except that they are injected with a benzyl benzoate castor oil vehicleonly. From the thus-obtained paw volumes, the edemainhibitory effect iscalculated in percent in the usual manner.

In these experiments, the comparison compound employed is theconventional 6a-fluoro-11,6,21-dihydroxy- 16a-methyl-1,4-pregnadiene3,20 dione. This compound causes, at a dosage of 1.0 rug/kg. of bodyWeight, an edema-inhibitory effect of about 40%. An edema-inhibitoryeffect of is always obtained when conducting these experiments, forexample, with 0.3 mg; 1.0 mg.; 3.0 mg.; or mg. per kg. of body weight ofthe methyl ester of 6a-flu0IO-1 lB,20u -dihydroxy-3 -oxol 6u-methyl-1,4-pregnadien-21-oic acid, the methyl ester of Got-fluoro- 11;8,20 3dihydroxy 3-oxo l6a-methyI-L4-pregnadien- 2l-oic acid, the butyl esterof 6a-fluoro1l,8,20u -dihydroxy-3-oxo-16cx-methyl-1,4-pregnadien-2l-oicacid, or the butyl ester of 6a-fluoro-l1,8,20,8-dihydroXy-3-oxo-l6amethyl-1,4-pregnadien 21 oic acid. Thus, thesecompounds exhibit no measurable systemic anti-inflammatory effect.

For the determination of the thymolytic effect, SPF rats weighing 70-110g. are adrenalectomized under ether narcosis. Six animals form each testgroup, each receiving subcutaneous injections, over a period of 3 days,of the selected amount of the test compound dissolved in a mixture of29% benzyl benzoate and 71% castor oil. On the fourth day, the animalsare sacrificed and the weight of their thymus is determined. The controlanimals are treated in the same way, but receive only the benzylbenzoatecastor oil vehicle. From the thus-obtained thymus weights, thethymolytic effect is calculated in percent in the usual manner.

The standard compound again is60t-fillOIO-11fi,21-dihydroxy-l6u-methyl-1,4-pregnadiene-3,20-dione,effecting, at a dosage of 1.0 mg/kg. of body weight, an approximately35% thymolysis. 0% thymolytic effect is obtained when conducting thesesame experiment with 0.3 mg.; 1.0 mg.; 3.0 mg; and 10 mg, per kg. ofbody weight of the methyl ester of 6a-fiuoro-11B,20a-dihydroxy-3-oxo-16amethyl-1,4-pregnadien-2l-oic acid, the methyl esterof 6afluoro 1l[3,20fl -dihydroxy-3-ox0-16a-methyl-1,4-pregnadien-2l-oicacid, the butyl ester of 6ufil1OI0-11fl'20a-dlhydroxy-3-oxo-l6a-methyl-1,4-pregnadien-21-oic acid and the butylester of fiu-fiuoro-llp,20fi -dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid.

The fact that the compounds of general Formula I do not possess systemicside effects can likewise be demonstrated with the aid of theeosinophile test, the glycogen test or the sodium-potassium retentiontest.

Thus, compounds of this invention which have been tested exhibitexcellent topical anti-inflammatory activity but not systemic activity.Therefore, these compounds are suitable for the treatment of skininflammations and surprisingly are entirely inactive systemically.

8v The corticoids hitherto employed for the treatment of skininflammations possess, in addition to the topical activity, systemiceffects. These corticoids can enter the 1 bloodstream even upon topicalapplication, due to resorption through the inflamed skin or due to skininjuries, Where they undesirably affect, as hormone-active substances,the body functions in a great variety of Ways.

This disadvantage does not exist with the compounds of the presentinvention, which are topically active but systemically ineffective.Therefore, they have advantages for the local treatment of inflammationsover conventional corticoids. Consequently, these substances can beapplied topically Without danger of side-effects to infants, pregnantfemales and diabetics, wherein the topical treatment with conventionalcorticoids generally is avoided in view of the danger of systemicside-effects.

The novel compounds are suitable, in combination with the excipientscustomary in galenic pharmacy, for the local treatment of contactdermatitis, eczemas of a wide variety of types, neurodermatitis,erthrodermia, burns, pruritus vulvae et ani, rosacea, erythematodes,cutaneus, psoriasis, lichen ruber planus et verrucosus, and similar skindiseases.

The drug specialties are produced in the usual manner, by converting theeffective agents together with suitable additives into the desired formof application, such as, for example, solutions, lotions, ointments,creams, aerosols and plasters. In the thus-formulated medicines, theconcentration of effective agent is dependent on the form ofapplication. In case of lotions and ointments, an effective agentconcentration of 0.001% to 1% is preferably employed.

The topically active, but systemically inactive compounds of thisinvention can be utilized not only as drugs but also for the manufactureof cosmetic preparations in combination With the usual vehicles andscent cOrnpOundS.

The 20-hydroxy steroids of general Formula I are also valuable asintermediates, preferably for the production of compounds of generalFormula IV CHzOH =0 --OH Z R1 A it Zinc Acetate Glacial Acetic Acid CHlOCOCH3 H"-R1 Z W B I r CHO IIIO

In the above formulae, A-B, X, Y, Z and R have the values given inFormula I.

This reaction can be conducted, for example, by dis solving a steroid ofFormula V in glacial acetic acid, mixing the solution with zinc acetateand heating under reflux. The thus-obtained mixture of compounds IIIband IIIc can be employed, without isolating the individual compounds,directly as starting material for the process of this inventionaccording to method (b) Without further elaboration, it is believed thatone skilled in the art can, using the preceding description, utilize thepresent invention to its fullest extent. The following preferredspecific embodiments are, therefore, to be construed as merelyillustrative, and not limltative 0f the remainder of the disclosure inany way whatsoeve Example 1 A solution of 11.3 g. of 6a-fiuoro-113,21-dihydroxyl6u-methyl-l,4-pregnadiene-3,20-dione in 500 ml. ofabsolute methanol is mixed with 3.0 g. of copper(II) acetate in 500 ml.of absolute methanol. The solution is stirred at room temperature for170 hours, then filtered, and concentrated under vacuum. The residue ismixed with ammonium hydroxide solution and extracted with methylenechloride. The organic phase is washed, dried over sodium sulfate, andconcentrated under vacuum. The remaining product is chromatographed on1.3 kg. of silica gel. After recrystallization from acetonehexane, oneobtains, with 6-7% acetone-methylene chloride, 1.40 g. of the methylester of 6a-fluoro-11B,20u dihydroxy-3-oxo-l6amethyl-1,4-pregnadien-2l-oic acid, m.p. 191192 C. [a] =O (chloroform).With 8- 10% acetone-methylene chloride, after recrystallizing theproduct twice from acetone-hexane, one obtains 2.9 g. of the methylester of 6a-fluoro-l1,6,20p -dihydroxy-3-oxo-l6a-methyl-1,4-pregnadien-2l-oic acid, mp. 128- 130 C. [a] =+2Z(chloroform).

Example 2 6.0 g. of 6a-flllOIO-1 13,21-dihydroxy-16wmethyl-1,4-pregnadiene-3,20-dione is allowed to stand in 180 ml. of n-butanol with1.6 g. of copper(II) acetate for 8 days.

The reaction product is worked up analogously to Example 1. The crudeproduct is chromatographed on 350 g. of silica gel. With 9-11%acetone-methylene chloride, after recrystallization from acetone-hexane,960 mg. of the butyl ester of 6a-fiuoro-1lB,20a -dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-2l-oic acid is obtained, m.p. 144-145 C. [a]=-=+3.4 (chloroform).

With 11-13% acetone-methylene chloride, 1.9 g. of a mixture of the butylesters of 6ocfil10I0-11}3,20a-dlhydroxy-3-oxo-16a-methyl-1,4-pregnadien-2l-oic acid and of 6afiuoro-l1,3,20B -dihydroxy-3-oxo-16a-methyl-1,4- pregnadien-Zl-oic acidis obtained by elution. With 13- 15%, after recrystallization fromacetone-hexane, one obtains 1.71 g. of the butyl ester of6a-flLl0I'0-11B,20fl dihydroxy-3-oxo-16u-methyl-1,4-pregnadien-2l-oicacid, m.p. 176-l77 C. [u] =-|12 (chloroform).

Example 3 A mixture of 8.2 g. of6a-fiuoro-9a-chloro-1113,2l-dihydroxy-l6a-methyl-1,4-pregnadiene-3,20-dione,200 ml. of isobutanol, and 4.1 g. of copper(II) acetate is heated on asteam bath for 53 hours and worked up as described in Example 1. Thecrude product is chromatographed on 400 g. of silica gel. With 67%acetone-methylene chloride, after recrystallization from acetone-hexane,one obtains 1.00 g. of the isobutyl ester of6oc-fll10IO-9occhloro-l1B,20ix -dihydroxy 3oxo-16u-methyl-1,4-pregnadien-Zl-oic acid, m.p. 189 C. [a] =-I48(dioxane). After recrystallization from acetone-hexane, with 8-10%methylene chloride-acetone, 2.1 g. of the isobutyl ester of6ix-fluoro-9u-chloro-115,20fl -dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid is obtained, mp. 215-216 C.[a] =|39 (dioxane).

Example 4 16.0 g. of 6a,9a-difluoro-l1 3,21-dihydroxy-l6a-methyl-1,4-pregnadiene-3,20-dione, 8 g. of copper(II) acetate, and 1000 ml. ofmethanol are reacted, worked up, and chromatographed as described inExample 1. After once recrystallizing from hexane-acetone, there isproduced with 68% acetone-methylene chloride 1.1 g. of the methyl esterof 6a,9a-difiuoro-1lB,20u -dihydroxy-3-oxo-16a-methyl-l,4-pregnadien-2l-oic acid, m.p. 174 C. [a] :|21 (dioxane).With 9-11% acetone-methylene chloride, after recrystallization fromacetone-hexane, one produces 5.3 g. of the methyl ester of60,9u-difluoro-l1p,20fl -dihydroxy-3-oxo-16ot-methyl 1,3 pregnadien 21oic acid, mp. 236 C [a] =+17 (dioxane).

Example 5 16.0 g. of6a-fluoro-2-chloro-115,2l-dihydroxy-l6amethyl-l,4-pregnadiene-3,20-dioneis heated with 8.0 g. of copper(II) acetate in 800 ml. of methanol underreflux to the boiling point for 50 hours. The reaction mixture is Workedup as disclosed in Example 1. The crude product is chromatographed on1.2 kg. of silica gel. After recrystallization from acetone-hexane, with89% acetone-methylene chloride, 550 mg. of the methyl ester of 6a-fluoro2 chloro-llB,20u -dihydroxy-3-oxo-16amethyl-1,4-pregnadien-21-oic acidis produced, mp. 230- 232 C. [a] =1.4 (dioxane). With l0l3%acetone-methylene chloride, 10.5 g. of a mixture of the methyl esters of6a-fluoro-2-chloro-1lfi,20a -dihydroxy-3-oxo-l6a-methyl-1,4-pregnadien-21-oic acid and of6afluoro-Z-chloro-l1,3,20fl -dihydroxy 3 oxo-16a-methyl-1,4-pregnadien-2l-oic acid is obtained in the form of a viscous,colorless oil, by elution.

After recrystallization from acetone-hexane, with 13- 14%acetone-methylene chloride, one produces 1.12 g. of the methyl ester of6u-fiuoro-2-chloro-11B,20B -dihydroxy-3-oxo-l6u-methyl-1,4-pregnadien-21-oic acid, m.p. 211-212 C. [a]=13 (dioxane).

Example 6 5.0 g. of 6rx-fiuoro-115,21-dihydroxy-l6a-methyl-1,4-pregnadiene-3,20dione is mixed with 250 ml. of isopropa- 1101 and 2.5 g.of copper(II) acetate. The mixture is refluxed for 6 hours and worked upas described in Example 1. The crude product is chromatographed on 250g. of silica gel. After recrystallization from acetone-hexane, oneobtains, with 79% acetone-methylene chloride, 309

mg. of the isopropyl ester of 6u-fluoro-l1fl,20a-dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid, m.p. 183-184 C.[a] =+8.5 (chloroform). After recrystallization from hexane'acetone,with 10-12% acetonemethylene chloride, 459 mg. of the isopropyl ester of6a-fluoro-11p,20;3 -dihydroxy 3 oxo 16a-methyl-1,4 pregnadien-Zl-oicacid is obtained, m.p. 182183 C. [a] -=+19 (chloroform).

Example 7 Under the reaction conditions set forth in Example 1, butusing isoamyl alcohol as the solvent, one produces from 16.0 g. of6u-fiuoro-11B,21-dihydroxy-16u-methyl 1,4-pregnadiene-3,20-dione 3.88 g.of the isopentyl ester of 60a fluoro-l1B,20a-dihydroxy-3-oxo-16a-methyl-1,4- pregnadien-Zl-oic acid, m.p. 7478 C.(from hexaneacetone), [cc] =+4.4 (chloroform), as well as 1.47 g. of theisopentyl ester of 6a-fluoro-l1/3,20B -dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid, m.p. 188 C. (fromhexane-acetone), [a] =+12 (chloroform).

Example 8 Under the reaction conditions described in Example 1, butusing tert.-butanol as the solvent, the yield, from 20.0 g. of6a-fluoro-115,2l-dihydroxy-16a-methyl-1,4- pregnadiene-3,20-dione, is9.8 g. of a mixture of the tert.- butyl esters of Goa-flUOIO-l1B,2Oa-dihydIOXy-3-OX0-16ozmethyl-1,4-pregnadien-21-oic acid and of6a-fluoro-11p, 20/3 dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oicacid, as well as 1.08 g. of the tert.-butyl ester of 6a-fluoro-1l,8,20fl -dihydroxy 3 oXo-16a-methyl-1,4-pregnadien- 21-oic acid, m.p.182 C. (from hexane-ace ne). [a] =+16 (chloroform).

Example 9 Using the reaction conditions described in Example 1, but withethanol being the solvent, one obtains from 8.6 g. of 6a,9a-difluoro11,8,21 dihydroxy 16a-methyl-1,4- pregnadiene-3,20-dione 6.1 g. of amixture of the ethyl esters of =6a,9otdiflll010 1lfi,20u-dihydroxy-3-oxo-16amethyl-1,4-pregnadien-21-oic acid and of6a,9ot-difluoro- 11p,20fl -dihydroxy-3-oxo-16a-methyl 1,4 pregnadien-2l-oic acid, as well as 3.1 g. of the ethyl ester of 601,90-difluoro-11fl,20B -dihydroxy 3 oxo 16a-methyl-14- pregnadiene-21-oicacid, m.p. 215-216 C. [a] -=-+l6 (dioxane).

Example 10 Under the reaction conditions described in Example 2, amixture of the butyl esters of 6a,9u-difluoro-11,6,20udihydroxy-3-oxo-16a-methyl 1,4 pregnadien-Zl-oic acid and of6a,9u-difluoro 116,20B dihydroxy-3-0xo-16umethyl-l,4-pregnadien-2l-oicacid is obtained from 60:,90:difiuoro-l1,8,21-dihydroxy-16a-methyl-l,4-pregnadiene-3,20-dione.

Example 11 Under the reaction conditions described in Example 1, using16.0 g. of=6a-fiuoro-9u-chloro-l15,21-dihydroxyl6a-methyl-1,4-pregnadiene-3,ZO-dione,the product is a mixture of 8.3 g. of the methyl esters of6ot-fi1lOIO-9occhloro-llfi,20a -dihydroxy-3-oxo-16a-methyl 1,4pregnadien-Zl-oic acid and of Got-fillOIO-9oc-Chl01O-115,2013dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-2l-oic acid, as well as 2.3 g.of the methyl ester of 6a-fiuOrO-9occhloro-11fl,20;8 -dihydrxy 3 oxo 16amethyl-1,4- pregnadiene-Zl-oic acid, decomposition point 245 C.

[a] '=+46 (dioxane).

Example 12 Under the reaction conditions set forth in Example 2, oneobtains from 8.0 g. of 6u-fluoro-9a-chloro-11,8,21-dihydroxy-l6wmethyl-1,4-pregnadiene-3,20-dione 1.35 g. of the butylester of 6a-fluoro-9a-chloro-11fl,20a-dihydroxy-3-oXo-l6u-methyl-1,4-pregnadien-21-oic acid, m.p. 175 C.(from hexane-acetone), [a] =|-33 (chloroform); and 640 mg. of the butylester of 6a-fluoro-9achloro-l1B,20fl -dihydroxy 3oxo-16a-methyl-1,4-pregnadien-21-oic acid, m.p. 196 C. (acetone-hexane),M113 +41 (chloroform).

Example 13 Under the reaction conditions described in Example 1, bututilizing cyclohexanol as the solvent, the yield, from 115,21 dihydroxy604,160; dimethyl-1,4-pregnadiene- 3,20-dione is a mixture of thecyclohexyl esters of 11,6, 2Oa -dihydroxy 3 0x0 601,16dimethyl-1,4-pregnadien-21-oic acid and of 11fi,20f3-dihydroxy-3-oxo-6a,160tdimethyl-1,4-pregnadien-21-oic acid.

Example 14 Using the reaction conditions set forth in Example 1, oneproduces from 19.8 g. of 6a-fluoro-9a,1lfi-dichloro- 2l-hydroxy16a-methyl 1,4 pregnadiene 3,20-dione 12.3 g. of the methyl ester of6a-fluoro-9a,1lfi-dichloro- 20B -hydroxy-3-oxo-16or-methyl 1,4pregnadien-21-oic acid, m.p. 217-219 C. (from acetone-hexane). =+82(dioxane).

Example 15 Under the reaction conditions described in Example 1, using18.1 g. of 601,1lfl-difluoro-9a-chloro-2l-hydroxy-16a-methyl1,4-pregnadiene-3,20-dione, one obtains 12.1 g. of the methylester of 611,115-difluoro-9a-chloro-20fi hydroxy-3-oxo-16a-methyl 1,4pregnadien-Zl-oic acid,

m.p. 246-247 C. (from acetone-hexane). [a] =34- (dioxane) Example 164.12 g. of Ga-fiUOI'O-l 13,21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione is dissolved in ml. of methanol and mixed with1.49 g. of copper(II) acetate. For 15 minutes, air is passed through thereaction mixture, and the latter is allowed to stand for 45 minutes. Thesolvent is distilled off and the crude product taken up in ethylacetate. The solution is washed with sodium bicarbonate solution, driedwith sodium sulfate, and concentrated by evaporation. The residue, whichis 6u-fluoro-11B,21-dihydroxy-Zl-methoxy methyl-1,4-pregnadiene-3,20-dione, is dissolved in 18 ml. of methanol and added to a mixture of 1.1liter of water and 20 ml. of 1N sodium hydroxide solution. Thesuspension is stirred for 48 hours at room temperature under an argonatmosphere. The reaction mixture is acidified with 1N hydrochloric acidand exhaustively extracted with methylene chloride. The extract is driedand evaporated, and the residue is recrystallized from acetone. Yield:1.03 g. of 6u-fluoro-11B, 20a -dihydroxy-3-oxo-16u-methyl1,4-pregnadien-21-oic acid, m.p. 250-251 C. (under decomposition). [M=+16 (dioxane).

Example 17 16.0 g. of 6a-fluoro-115,21-dihydroxy-l6a-methyl-1,4-pregnadiene-3,20-dione is reacted with hexanol under the conditionsdescribed in Example 1, thus obtaining 2.32 g. of the hexyl ester of6a-fiuoro-11,8,20a -dihydroxy-3-oxo- 1Gu-methyl-I,4-pregnadien-2l-oicacid, m.p. 99 C., [a] =+32 (chloroform); and 4.89 g. of the hexyl esterof Ga-fiuoro-l15,20B -dihydroxy-3-oxo-16a-methyl- 1,4-pregnadien-2l-oicacid, m.p. 162-169 C., [111 =+11 (chloroform).

Example 18 10.5 g. of 6u-fluoro-11/3,2l-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione is reacted with cyclohexanol under the conditionsset forth in Example 1, thus producing 2.29 g. of the cyclohexyl esterof 6u-fiuoro-11fl,20a dihydroxy-3-oxo-16ot-methyl 1,4-pregnadien-21-oicacid, m.p. 107 C., [a] =-{-12 (dioxane); and 3.85 g. of the cyclohexylester of 6a-fluoro11;8,20,8 -dihydroxy-3-oxo-l6zx-methyl-1,4-pregnadien-2l-oic acid, m.p. 228 C., [a] 14(dioxane) 13 Example 19 12.0 g. offia-fiuoro-l1,6,2l-dihydroxy-16a-methyl-1,4- pregnadiene-3,20-dione isreacted with decanol under the conditions set out in Example 1, thusobtaining 1.8 g. of the decyl ester of 6u-fluoro-11p,20a-dihydroxy-3-oxo- 16ix-methyl-1,4-pregnadien-2l-oic acid as a viscousOil, [a] =+8 (chloroform) and 2.67 g. of the decyl ester of 6ot-fiuoro11/3,20B -dihydroxy-3-oxo-16m-methyl-1,4- pregnadien-Zl-oic acid, m.p.123l25 C., [a] .=+13 (chloroform) Example 20 (a) 107.0 g. of90t-fl11OIO-11,3,17a,21tI'ihydl'OXy-160tmethyl-l,4-pregnadiene-3,20-dioneis dissolved in 2 liters of glacial acetic acid and mixed with 10.0 g.of zinc acetate containing water of crystallization. The reactionmixture is refluxed for 4 hours and then precipitated into 10 liters ofice water. The precipitate is filtered off and taken up in methylenechloride, which is thereupon washed neutral with water. The solvent isremoved by drying over anhydrous sodium sulfate and evaporation undervacuum, thus producing 112.0 g. of a mixture of 9a-fluoro 115,20dihydroxy-3-oxo-l6tx-methyl-l,4,17- (20)-pregnatrien-2l-al and 9a-fiuoro-11.fi-hydroxy-20- acetoxy-3-oxo-16a-methyl 1,4,17(20)-pregnatrien-21-alas a viscous oil.

(b) 108.0 g. of the above mixture is dissolved in 3 liters of methanoland mixed with a solution of 15.0 g. of potassium hydroxide in 30 ml. ofwater. The reaction mixture is refluxed for 1 /2 hours under an argonatmosphere, and then the methanol is distilled off under vacuum. Theremainder is taken up in 2 liters of water and 2 liters of methylenechloride and, for purposes of further purification, the aqueous phase isrepeatedly extracted with methylene chloride. The aqueous solution isacidified with 4N sulfuric acid and again extracted several times withmethylene chloride, which is thereupon dried over sodium sulfate. Afterevaporation of the solvent under vacuum, one obtains 52.0 g. of amixture of 9:1 fluoro-11p,2Ou -dihydroxy-3-ox0-16a-methyl-1,4-pregnadien-Zl-oic acid and 9a-fluoro-11fl,20 3-dihydroxy-3-oxo-l6ot-methyl-1,4-pregnadien-2l-oic acid as a solidcrystal cake.

(c) 36.0 g. of the just-described acid mixture is mixed with 200 ml. ofmethanol and cooled to C. In incremental portions, an ether solution ofdiazomethane in one liter of ether is added thereto, which ethersolution has been produced from 30 g. of nitrosomethyl urea bydecomposition with 40% potassium hydroxide solution. The mixture isstored at room temperature for one hour. The solvents are then removedunder vacuum, after gently eliminating the excess of diazomethane with 5ml. of glacial acetic acid. The residue is taken up in methylenechloride, and the solution is repeatedly washed with water. The reactionmixture is dried over anhydrous sodium sulfate, and the crude product ischromatographed on 750 g. of silica gel.

With 69% methylene chloride-acetone, 2.1 g. of the methyl ester of9a-flLlOIO-11B,20ot -dihydIOXy-3OX0-l60- methyl-1,4-pregnadien-2l-oicacid is eluted.

Recrystallized from acetone-hexane, the product amounts to 1.22 g., m.p.199.3 C. [a] =+2.8 (chloroform) With 10-12% methylene chloride-acetone,23.8 g. of a mixture of the 20w and 205-compounds is obtained byelution.

With 13-14% methylene chloride-acetone, the eluted product is 1.19 g. ofthe methyl ester of 9a-fiUOIO-llfi, 20fi -dihydroxy-3-oxo 16a methyl 1,4pregnadien 21-oic acid. The crude product is recrystallized fromacetone-hexane, thus producing 794 mg., mp. 206.5 C. [a] +23(chloroform).

Example 21 1.0 g. of the decyl ester of 6u-fluoro-11B,20B-dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid is dissolved in15 ml. of pyridine, and the solution is mixed with 3 ml. of aceticanhydride. The mixture is allowed to react overnight at room temperatureand then precipitated with 500 ml. of Water containing 50 g. of sodiumchloride. The precipitate is filtered off and taken up in methylenechloride. The solution is washed several times with water and dried overanhydrous sodium sulfate. After evaporation of the solvent, thereremains 1.12 g. of crude product which is chromatographed on 250 g. ofsilica gel. With 6-9% acetone-hexane, 680 mg. of the decyl ester of6a-fluoro-l1B-hydroxy-20B -acetoxy-3-oxo-16u-methyl-1,4-pregn'adien-21-oic acid is eluted which, afterevaporation of the solvents, forms an amorphous powder. Melting point:l29-13l C. [a] +24 (chloroform).

Example 22 500 mg. of the cyclohexyl ester of 6u-fluoro-11fl,20;8'dihydroxy-3-oxo 16a methyl 1,4 -pregnadien-2l-oic acid is reacted withthe reactants indicated in Example 21 and worked up under the sameconditions. After the crude product has been chromatographed andrecrystallized, one obtains 202 mg. of the cyclohexyl ester of 60afluoro 11B hydroxy 203 acetoxy-3-oxo-16amethyl 1,4 pregnadien-Zl-oicacid, m.p. 238.8 C. [a] =+22 (chloroform).

Example 23 900 mg. of the isopentyl ester of Mfume-1113,20dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-2l-oic acid is dissolved in 12 ml. of pyridine and mixed with 3 ml. of propionic acid anhydride. Themixture is allowed to react for 3 days and then precipitated with 300ml. of ice water containing sodium chloride. The precipitated product isfiltered off, taken up in methylene chloride, and washed, whereafter itis dried over anhydrous sodium sulfate and the solvent evaporated undervacuum. The crude product is recrystallized from acetone-hexane, thusobtaining 578 mg. of the isopentyl ester of 6u-(fluoro- 11,8-hydroxy ZOapropionyloxy-3-oxo-16a-methyl-l,4- pregnadien-Zl-oic acid, m.p. 148.2 C.[a] =+52 (chloroform) Example 24 As described in Example 23, 600 mg. ofthe isopentyl ester of fia-fiuoro-l1fi,20B -dihydroxy-3-oxo-16tx-methyl-1,4-pregnadien-21-oic acid, dissolved in pyridine, is reacted with 3 ml.of butyric acid anhydride. The reaction mixture is worked up asdescribed above and, after recrystallization of the crude product fromacetone-hexane, one obtains 526' mg. of the isopentyl ester of6u-fluorollp-hydroxy ZOB butyryloxy-B-oxo-l6u-methyl-l,4-pregnadien-Zl-oic acid, m.p. 194.6 C. [u] =+26 (chloroform) Example 25As described in Example 21, 1.10 g. of the hexyl ester of 60;fluoro-11,B,20a -dihydroxy-3-ox0l6a-methyl-1,4- pregnadien-Zl-oic acidin 10 ml. of pyridine is reacted with 2 ml. of acetic anhydride and thenworked up as described above. After purification by chromatography andrecrystallization from acetone-hexane, 846 mg. of the hexyl ester of 6ufluoro-ll/3-hydroxy-20 x -acetoxy-3-oxo-16u-methyl-1,4-pregnadien-2l-oic acid is obtained, mp. 159.9 C.[a]; =+50 (chloroform).

Example 26 600 mg. of the methyl ester of 6a,9u-difluoro-l1,B, 20a-dihydr0xy-3-oxo-1Got-methyl 1,4 pregnadien-Zloic acid is dissolved in20 m1. of pyridine and mixed with 2 ml. of butyric acid anhydride. Thereaction mixture is worked up as set forth in Example 22, and the crudeproduct is purified by crystallization from acetonehexane, thusobtaining 381 mg. of the methyl ester of 15 611,90: difluoro 11Bhydroxy-20a -butyry1oxy-3-oxo- 16a-methyl-1,4-pregnadien-21-oic acid,m.p. 188.4" C. [a] 49 (chloroform).

Example 27 650 mg. of the methyl ester of 6a,9a-difluoro-11fl,20,Bdihydroxy 3 oxo-16ot-methyl-1,4-pregnadien-21-oic acid is dissolved in15 ml. of pyridine and mixed with 3 ml. of caproic acid anhydride. After6 days of reaction at room temperature, the reaction mixture is workedup as set forth in Example 23. After recrystallization of the crudeproduct from acetone-hexane, one produces 710 mg. of the methyl ester of60,9a-difl1lOIO-1IB-hYdIOXY- 20/3 -hexanoyloxy 3 oxo 16amethyl-1,4-pregnadien- 21-oic acid, m.p. 83.6 C. [a] =+17.2(chloroform).

Example 28 700 mg. of the ethyl ester of 6u,9a-difluoro-11/8,20;8dihydroxy 3 oxo-16a-methyl-1,4-pregnadien-21-oic acid in 15 ml. ofpyridine and 3 ml. of caprylic acid anhydride are allowed to stand atroom temperature for 6 days and then worked up as described in Example23. After recrystallization from acetone-hexane, one obtains 561 mg. ofthe ethyl ester of 6a,9a-difluoro-11,6-hydroxy-2O 8octanoyloxy-3-oxo-16a-methyl 1,4 pregnadien 21 oic acid, m.p. 163.0 C.[a] +29 (chloroform).

Example 29 700 mg. of the methyl ester of 6cc-fiI101'0-9a,113-dichloro20fi -hydroxy 3 oxo-l6a-methyl-1,4-pregnadien- 21-oic acid,dissolved in 15 ml. of pyridine, and 2 ml. of valeric acid anhydride arereacted and worked up as described in Example 23. After recrystallizingthe crude product from acetone-hexane, 780 mg. of the methyl ester of6oLfill0I0-9a,11fl-dihl0l0 20,8 valeryloxy 3 oxo-IGu-methyl-1,4-pregnadien-21-oic acid is obtained, m.p. 217.1 C. (underdecomposition). [a] ='+73 (chloroform).

Example 30 700 mg. of the hexyl ester of 6a-fluoro-11/3,20/3-dihydroxy-3-oxo-16u-methyl-1,4-pregnadien-21-oic acid is dissolved in15 ml. of pyridine and reacted with 2 ml. of propionic acid anhydride.The reaction mixture is worked up and purified by chromatography asdescribed in Example 21, thus obtaining 570 mg. of the hexyl ester of6u-fluoro-11B-hydroxy ZOfi propionyloxy 3 oxo-1-6a-methyl-1,4-pregnadien-21-oic acid, m.p. 124.5 C. [a] ='+23(chloroform).

Example 31 250 mg. of the methyl ester of 6a-fluoro-11B,2Ou-dihydroxy-3-oxo-1-6a-methyl-1,4-pregnadien-21-oic acid is dissolved in3 ml. of pyridine and mixed with 1 ml. of acetic anhydride. The reactionmixture is worked up further as described in Example 21. Afterrecrystallization of the crude product, purified by chromatography, fromacetone-hexane, one obtains 143 mg. of the methyl ester ofu-fluoro-llB-hydroxy 201x 7 acetoxy 3oxo-16amethyl-1,4-pregnadien-21-oic acid, m.p. 167.6 C. [a] 3(chloroform).

Example 32 250 mg. of the methyl ester of 6a-fluoro-11fi,205-dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid is dissolved in 3ml. of pyridine and mixed with 1 ml. of acetic anhydride. The reactionmixture is worked up as set forth in Example 23. By recrystallizing thecrude prod not from acetone-hexane, 145 mg. of the methyl ester of6m-fiuoro-l1fi-hydroxy-20/3 -acetoxy 3 oxo-16a-methyl-1,4-pregnadien-21-oic acid is obtained, m.p. 185.3 C. [0c] ='+31(chloroform).

16 Example 33 As described in Example 23, 1.03 g. of the butyl ester of6a-fiuoro-11fi,20fi -dihydroxy 3 oxo-16a-methyl-1,4- pregnadien-Zl-oicacid, dissolved in 8 ml. of pyridine, is allowed to react with 2 ml. ofbutyric acid anhydride. After the reaction mixture has been Worked upand crystallized from acetone-hexane, the yield is 784 mg. of the butylester of 6u-fluoro-11fl-hydroxy-Z0B -butyryloxy-3-oxo-l6u-methyl-1,4pregnadien-21-oic acid, m.p. 183 C. [a] +28.5(chloroform).

Example 34 700 mg. of the tert.-butyl ester of 6u-fluoro-115,20Bdihydroxy 3 oxo-l6a-methyl-1,4-pregnadien-21-oic acid is mixed with 10m1. of pyridine and 3 ml. of butyric acid anhydride. After 5 days, thereaction mixture is worked up as indicated in Example 21. Afterrecrystallization of the crude product from acetone-hexane, one obtains104 mg. of the tert.-butyl ester of 6a-fluoro-11fl-hydroxy- 20 8-butyryloxy 3 oxo-16 ocmethyl-1,4-pregnadien-21- oic acid, m.p. 202.2 C.'[a] +23 (chloroform).

Example 35 1.32 g. of the methyl ester of 60t-fluOrO-11fi,2O06-dihydroxy 3 oxo-16u-methyl-1,4-pregnadien-21-oic acid, dissolved in 50ml. of methanol, is mixed at room temperature with 5 ml. of 1N sodiumhydroxide solution. After 20 hours, the mixture is diluted with 200 ml.of water and repeatedly extracted with methylene chloride. The aqueousphase is thereupon acidified with 10 ml. of 1N sulfuric acid andrepeatedly extracted with methylene chloride. The latter is dried oversodium sulfate and evaporated under vacuum. The residue is trituratedwith a small amount of ethyl acetate. After allowing the mixture tostand for a period of time, the thus-produced crystallized product isvacuum-filtered, thus obtaining 225 mg. of 6a-fluoro-115,20a -dihydroxy3 oxo-16a-methyl-1,4- pregnadien-Zl-oic acid, m.p. 252.3 C. (underdecomposition). [0c] =+15.8 (chloroform).

Example 36 4.1 g. of the methyl ester of 6oc-fl1lO1O11[i,2O 9 -dihydroxy-3-oxo-16ix-methyl-1,4-pregnadien-21-oic acid is dissolved in ml.of methanol and mixed with 5 ml. of 1N sodium hydroxide solution at roomtemperature. The reaction mixture is Worked up as described in Example35, thus obtaining 3.10 g. of 6a-fiuoro-11 8,2OB-dihydroxy-3-oxo-16ix-methyl-1,4-pregnadien-21-oic acid as a viscousoil. [0c] =|23 (dioxane).

Example 37 2.15 g. of 60: fiuoro 11p,20 8 -dihydroxy-3-oxo-16amethyl 1,4pregnadien-21-oic acid is dissolved in 100 ml. of acetone and mixed, atroom temperature, with 1 ml. of 70% strength perchloric acid. After areaction time of 5 days, the product is precipitated with 2 liters ofwater containing sodium chloride which is filtered off from theprecipitate. The latter is taken up in methylene chloride, and thesolution is washed with saturated sodium bicarbonate solution and withwater. The mixture is dried over sodium sulfate, and the solvent isevaporated under vacuum. For purposes of purification, the crude productis chromatographed on 250 g. of silica gel. With 710% acetone hexane,960 mg. of 6a-fl'uoro-11 8-hydroxy-20fi 21 isopropylidenedioxy1Got-methyl-1,4-pregnadiene-3, 21-dione is obtained by elution. Byrecrystallization from acetone-hexane, 412 mg. of crystals are obtainedwhich melt at 276.5 C. under decomposition. [a] =;-|-7.8 (chloroform)Example 38 490 mg. of 60 -fluoro- 11fi,20u-dihydroxy-3-oxo-16umethyl-1,4-pregnadien-21-oic acid is dissolved in 10ml. of acetone and mixed with 2 drops of 70% perchloric acid at roomtemperature. After 22 hours, the reaction 17 mixture is worked up andpurified as set forth in Example 37. After recrystallization of thechromatographed product, one obtains 152 mg. of6a-fluoro-1IB-hydrOXy-ZOa 21isopropylidenedioxy-16a-methyl-1,4-pregnadiene-3,21- dione, m.p. 192.1C. (under decomposition). M1 +14 (chloroform).

Example 39 15.1 g. of a mixture of 9a-fluoro-11B,20a -dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-2l-oic acid and 9a-fluoro- 115,20Bdihydroxy 3-oxo-16u-methyl-1,4-pregnadien- 21-oic acid is dissolved in750 ml. of acetone and mixed, at room temperature, with 1 ml. of 70%perchloric acid. After 5 days, the recation mixture is worked up asdisclosed in Example 37. The crude product (12.1 g) is chromatographedon 750 g. of silica gel. With 68% acetone-methylene chloride, 1.74 g. of9a-fiuoro-11B-hydroxy 20/3 ,21 isopropylidenedioxy 16a methyl-1,4-pregnadiene-3,21-dione is eluted, melting at 276.3 C. uponcrystallization from acetone-hexane. [u] =|-6.4 (chloroform) With 8-10%acetone-methylene chloride, one obtains 9.3 g. of a mixture of the ZOaand ZOOt -COUIPOUHdS.

With 11-13% acetone-methylene chloride, 1.3 g. of 9afiuoro 11,8hydroxy-20a ,2l-isopropylidenedioxy-16amethyl-l,4-pregnadiene-3,2l-dioneis eluted which, when crystallized from acetonehexane, melts at 257 .0C. under decomposition. [a] +29 (chloroform).

Example 40 900 mg. of the methyl ester of 9a-fluoro-11fi,20a-dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid is dissolved in10 ml. of pyridine and mixed with 2 ml. of butyric acid anhydride. Afterallowing the reaction mixture to stand for two days at room temperature,it is worked up as indicated in Example 23 and purified by a singlecrystallization of the crude product, thus producing 588 mg. of themethyl ester of 9a-fluoro-11fl-hydroxya butyryloxy3-oxo-16a-methyl-1,4-pregnadien-21- oic acid, m.p. 187.4 C. [a] =+54(chloroform).

Example 41 400 mg. of the methyl ester of 9a-fiuoro-11/3,20 3-dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid is dissolved in10 ml. of pyridine and mixed with 2 ml. of butyric acid anhydride. Thereaction mixture is allowed to stand for two days at room temperatureand then worked up as set forth in Example 23. By a singlecrystallization of the crude product, one obtains 378 mg. of the methylester of 9a fluoro-11B-hydroxy-Z0fi -butyryloxy-3oxo-16a-methyl-l,4-pregnadien-21-oic acid, m.p. 182.9 C. [a] =+36(chloroform).

Example 42 Under the conditions set forth in Example 2, 20.0 g. of 6afluoro 115,21 dihydroxy-16ot-methyl-4-pregnene- 3,20-dione is recated,thus obtaining 15.3 g. of a mixture of the butyl esters of6a-fluoro-11fl,20a -dihydroxy-3- oxo-16a-methyl-4-pregnen-2l-oic acidand of 6a-fiuoro- 1113,20 8 dihydroxy-3oxo-16a-methyl-4-pregnen-2l-oicacid, and 300 mg. of the butyl ester of 6a-fiuoro-11fl,20u

dihydroxy-S-oxo-16a-methyl-4-pregnen-2l-oic acid, m.p. 94 C. (frommethylene chloride-diisopropyl ether),

(chloroform), as well as 2.8 g. of the butyl ester of 6a- -fluoro11,8,20,6 -dihydroxy-3-oxo-16a-methyl-4-pregnen- 21-oic acid, m.p. 139C. (from acetone-hexane),

]n (chloroform) Example 43 Under the conditions described in Example 1,one obtains from 7.0 g. of 115,21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione, 5.8 g. of a mixture of the butyl esters of11B,20a -dihydroxy-3-oxo-16u-methyl-1,4-pregnadien-Zl-oic acid and of11,B,2'0,8 -dihydroxy-3-oxo-16ccmethyl-1,4-pregnadien-21-oic acid, aswell as the pure compounds: 230 mg. of the butyl ester of 11;8,20a-dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-2l-oic acid, m.p. 166.3 C.(from methylene chloride-diisopropyl ether), [a] =+2.7 (chloroform); and880 mg. of the butyl ester of 115205 1dihydroxy-3-oxo-16a-methyl-1,4-pregnadien 21 oic acid, m.p. 177.7 C.(from acetonehexane), [a] =|-12.7 (chloroform).

Example 44 Under the reaction conditions described in Example 1, 10.0 g.of 6a,9a-difiuoro-11,8,21-dihydroxy-16u-methyl-1,4-pregnadiene-3,20-dione is recated with 5 g. of copper(II) acetateand 250 ml. of n-butanol. After chromatographing the crude product, thefollowing compounds are isolated: 1.05 g. of the butyl ester of6a,9a-difluoro- 11fl,2Ooc dihydroxy 3-oxo-16u-methyl-1,4-pregnadien-21-oic acid, m.p. 143 C. (ether), [a] ='+6.1 (chloroform), and 1.37 g.of the butyl ester of 601,90:- difiuoro 115305 dihydroxy 3oxo-16a-methy1-1,4- pregnadien-Zl-oic acid, m.p. 187.3 C.(acetone-hexane), [a] =+12.8 (chloroform).

Example 45 Under the reaction conditions set forth in Example 1, 10.0 g.of 60a fluoro 115,2l-dihydroxy-la-methyl-1,4- pregnadien-3,20-dione isreacted with 6 g. of copper(II) acetate and 300 ml. of ethylene glycol.After chromatography of the crude product, 1.81 g. of the 2-hydroxyethylester of 6a-fluoro-11fi,20,8 -dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid is produced, m.p. 205 C. (acetone-hexane),[a] =|54 (pyridine).

Example 46 2.0 g. of the butyl ester of 6a-fluoro-11 3,20fl -dihydroxy 3oxo-l6a-methyl-1,4-pregnadien-21-oic acid is dissolved in 35 ml. ofbenzyl alcohol and mixed with 50 mg. of potassium tert.-butylate. Themixture is heated on a steam bath under an argon atmosphere for 28hours. The reaction mixture is diluted with methylene chloride, washedwith dilute acetic acid and water, and dried. The solvent is distilledoff under vacuum and the residue chromatographed on silica gel, thusobtaining 431 mg. of the benzyl ester of 6a-fluoro-11B,20B-dihydroxy-3-oxo-16amethyl-1,4-pregnadien-21-oic acid, m.p. 216 C.(acetonehexane), [a] =+57 (pyridine).

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

1. A pregnanoic acid derivative of the formula COOR:

H OR:

wherein OR,,, is in the 061:1 or fl t-position; A-B is CH CH CH=CH- orCCl=CH--; R is hydrogen or methyl; R is hydrogen or the acyl radical ofa physiologically acceptable acid of up to 15 carbon atoms and R ishydrogen or hydrocarbon of up to 18 carbon atoms or R and R collectivelyare dialkylmethylene wherein each alkyl is of 1-4 carbon atoms orcycloalkylidene of to 7 ring carbon atoms; X is hydrogen, halogen ormethyl; Y is hydrogen or halogen; Z is hydroxy or a halogen atom havingthe same atomic weight no greater than Y; and wherein at least one of X,Y and R is other than hydrogen.

2. A compound of Claim 1 wherein R is H, alkanoyl of 1-8 carbon atomsand R is H or alkyl of 1-4 carbon atoms or cycloalkyl of 5 or 6 ringcarbon atoms or, collectively R and R are dialkylmethylene wherein eachalkyl is of 1-4 carbon atoms or cyclopentylidene or cyclohexylidene.

3. A compound of Claim 2 wherein R is methyl.

4. A compound of Claim 3 wherein A--B- is CH=CH.

5. A compound of Claim 4 wherein X is H or F and Y and Z are H, C1, orF.

6. A compound of Claim 1, methyl ester of 6a-fiuoro- 11p,20a-dihydroXy-3-oxo 16cc methyl-1,4-pregnadien- 21-oic acid.

7. A compound of Claim 1, methyl ester of 6OC-fiuOIO- llp,20fidihydroxy-3-oxo 16a methyl-1,4-pregnadien- 21-oic acid.

8. A compound of Claim 1, butyl ester of Scx-flLIOIO- 11;8,20a-dihydroxy-3-oxo 16a methyl-1,4-pregnadien- 21-oic acid.

9. A compound of Claim 1, butyl ester of 6a-fluoro- 11p,20p-dihydroxy-3-oxo 16oz methyl-1,4-pregnadien- 21-oic acid.

10. A compound of Claim 1, isobutyl ester of 60t-flll0-ro-9u-chloro-11p,20a -dihydroxy-3-oxo-16a-methyl 1,4- pregnadien-Zl-oicacid.

11. A compound of Claim 1, isobutyl ester ofGot-fluoro-9a-chloro-11p,20/3 -dihydroxy-3-oxo-16u-methyl 1,4-pregnadien-Zl-oic acid.

12. A compound of Claim 1, methyl ester of 60:,9m-difluoro-llp,20adihydroxy 3 oxo-16a-methyl-L4-pregnadien-Zl-oic acid.

13. A compound of Claim 1, methyl ester of 60:,9ot-dlfluoro-11fi,20/8--dihydroxy 3 oxo-l6u-methyl-1,4-pregnadien-21-oic acid.

14. A compound of Claim 1, methyl ester of 6a-fluoro-2-chloro-11p,20a-dihydroxy 3 oxo-16a-methyl-1,4- pregnadien-Zl-oic acid.

15. A compound of Claim 1, methyl ester of Get-fluo--ro-2-chloro-11,6,20,8 -dihydroxy 3 OXO-16ot-I1'16thYl-L4-pregnadien-Zl-oic acid.

16. A compound of Claim 1, isopropyl ester of 6a-fluoro-l1p,20a-dihydroxy-3-oxo 160a methyl-1,4-pregnadien-21-oic acid.

17. A compound of Claim 1, isopropyl ester of 6u-fluoro-l1B,205-dihydroxy-3-oxo-16a-methyl-1,4 pregnadien- 2l-oic acid.

18. A compound of Claim 1, isopentyl ester of Gee-fluoro-11p,20u-dihydroxy 3 oxo-l6ot-methyl-1,4-pregnadien-Zl-oic acid.

19. A compound of Claim 1, isopentyl ester of 6a-fiuoro-l1fl,20B-dihydroxy-3-oxo-16a-methyl-1,4 pregnadien- 21-oic acid.

20. A compound of Claim 1, tert.-butyl ester of 6a-fluoro-l1f3,20a-dihydroxy-3-oxo-16u-methyl-1,4 pregnadien- 21-oic acid.

21. A compound of Claim 1, tert.-buty1 ester of Got-fluoro-llfiiop-dihydroxy 3 oxo-16ot-methyl-1,4-pregnadien-21-oic acid.

22. A compound of Claim 1, ethyl ester of 60,9u-difluoro-11/3,20a-dihydroxy 3 oxo-16a-methyl-l,4-pregnadien-21-oic acid.

23. A compound of Claim 1, ethyl ester of 60,9ot-dlfluoro-11,20B-dihydroxy 3 oxo-16u-methyl-L4-pregnadien-Zl-oic acid.

24. A compound of Claim 1, butyl ester of 6a,9ot-difluor0-11fl,20a-dihydroxy 3 oxo-16ot-methyl-L4-pregnadien-Zl-oic acid.

25. A compound of Claim 1, butyl ester of 6,a,9a-difluoro-11p,20fi-dihydroXy 3 oxo-16a-methy1-L4-pregnadien-21-oic acid.

26. A compound of Claim 1, methyl ester of Got-fluoro-9a-chloro-1lfl,20u-dihydroxy-3-oxo-16a-methyl 1,4- pregnadien-Zl-oic acid.

27. A compound of Claim 1, methyl ester ofGot-fluoro-9a-chloro-11fl,20fi -dihydroxy3-oxo-l6a-methyl 1,4-pregnadiene-Zl-oic acid.

28. A compound of Claim 1, butyl ester of 6u-fluoro- 9a-chloro-l1,8,20ot-dihydroxy 3 oxo-l6ot-methyl-1,4- pregnadiene-Zl-oic acid.

29. A compound of Claim 1, butyl ester of Get-fluoro-9u-chloro-11B,2()/3 -dihydroxy 3 oxo-l6u-methyl-1,4 pregnadiene-Zl-oicacid.

30. A compound of Claim 1, cyclohexyl ester of 115, 20a-dihydroxy-3-oxo-6u,16a-dimethyl 1,4 pregnadien- 21-oic acid.

31. A compound of Claim 1, cyclohexyl ester of 11,3, 2flfi-dihydroxy-3-oxo-6a,16a-dimethyl 1,4 pregnadien- 2l-oic acid.

32. A compound of Claim 1, methyl ester of 6oz-flll010-904,1lfi-dichloro-20fi hydroxy 3 oxo-16a-methyl-1,4- pregnadiene-Zl-oicacid.

33. A compound of Claim 1, methyl ester of 60:,11/3-difluoro-9a-chloro-20fl -hydroxy 3 ox0-16a-n1ethyl-1,4-pregnadiene-Zl-oic acid.

34. A compound of Claim 1, 6a-fluor0-1lB,20a-dihydroxy-3-oxo-16u-methyl-1,4-pregnadien-21-oic acid.

35. A compound of Claim 1, hexyl ester of 6a-fluoro- 11/3,20u-dihydroxy-3-oxo 16a methyl-1 ,4-pregnadien- 21-oic acid.

36. A compound of Claim 1, hexyl ester of 6a-fluoro- 11fl,20/3-dihydroxy-3-oxo 16oz methyl-1,4-pregnadien- 21-oic acid.

37. A compound of Claim 1, cyclohexyl ester of 60cfiuoro 11,8,20a-dihydroxy-3-oxo-16u-methyl-1,4-pregnadien-Zl-oic acid.

38. A compound of Claim 1, cyclohexyl ester of 6afluoro-llfi,20fl-dihydroxy 3 oxo-16a-methyl-l,4-pregnadien-Zl-oic acid.

39. A compound of Claim 1, decyl ester of 6a-fiu0r0- 1lfl,20a-dihydroxy-3-oxo 16a methyl-1,4-pregnadien- 21-oic acid.

40. A compound of Claim 1, decyl ester of 6a-fluoro- 11B,2Ofl-dihydroxy-3-oxo 160a methyl-1,4-pregnadien- 21-oic acid.

41. A compound of Claim 1, 9a-fluoro-11B,20a-dihydroxy-3-oxo-1a-methyl-1,4-pregnadien-21-oic acid.

42. A compound of Claim 1, 9a-fluor0-11 8,20;8-dihydroxy-3-0Xo-1Ga-methyI-IA-pregnadien-Zl-oic acid.

43. A compound of Claim 1, methyl ester of t-fiIlOI'O- l1,B,20a-dihydroxy-3-oXo 16a methyl-1,4-pregnadien- 21-oic acid.

44. A compound of Claim 1, methyl ester of 9a-fluoro- 115,20/3dihydroxy-S-oxo 16a methyl-1,4-pregnadien- 2l-oic acid.

45. A compound of Claim 1, decyl ester of 6a-flll0l0- llp-hydroxy-20 3acetoxy 3 oxo-l6u-methyl-1,4-pregnadien-21oic acid.

46. A compound of Claim 1, cyclohexyl ester of 6afluoro-l 1B-hydroxy-203 -acetoXy 3 oxo-16a-methyl-1,4- pregnadien-Zl-oic acid.

47. A compound of Claim 1, isopentyl ester of 6afluoro-l1,8-hydroxy-20a-propionyloxy-3-oxo-1 6m methyl-1,4-pregnadien-21-oic acid.

4.8. A compound of Claim 1, isopentyl ester of 6afluoro-l1p-hydrOXy-ZOB-butyryloxy 3 0XO-160t-I11Cthyl- 1,4-pregnadien-21-oic acid.

49. A compound of Claim 1, hexyl ester of 6a-fll101'0- 11fl-hydroXy-20a-acetoxy 3 oxo-16u-methyl-L4-pregnadien-Zl-oic acid.

50. A compound of Claim 1, methyl ester of6a,9a-difluoro-l1,B-hydroxy-Z0a -butyryloxy 3 oXo-16a-methyl-1,4-pregnadien-21-oic acid.

51. A compound of Claim 1, methyl ester of60:,9oc-dlfiuoro-l1B-hydroxy-Z0fl -hexanoyloxy-3-oxo-16amethyl-1,4-pregnadien-21-oic acid.

52. A compound of Claim 1, ethyl ester of60;,9a-difluoro-l1,B-hydroxy-20fi -octanoyloXy-3oxo-l6a methyl1,4-pregnadien-2l-oic acid.

53. A compound of Claim 1, methyl ester of 6a-fil101'0-9a,1LB-dichloro-20,8 -valeryloxy-3-oxo-IGa-methyl 1,4- pregnadien-Zl-oicacid.

54. A compound of Claim 1, hexyl ester of 6u-fluoro- 1lB-hydroxy-Z0fi-propio'nyloxy 3 OXO-16oc-II16thYl-L4- pregnadien-Zl-oic acid.

55. A compound of Claim 1, methyl ester of 6a-fiuoro- 1IB-hydroXy-ZOu-acetQXy 3 oxo-16a-methyl-1,4-pregnadien-21-oic acid.

56. A compound of Claim 1, methyl ester of 6a-fiuoro- II S-hydrOXy-ZOB-acetOXy 3 oXo-16a-methyl-1,4-pregnadien-Zl-oic acid.

57. A compound of Claim 1, butyl ester of 6a-fluorollfi hydroxy-20fi-butyryloxy 3 OXO-16oc-m6thY1-L4- pregnadien-Zl-oic acid.

58. A compound of Claim 1, tert.-butyl ester of6afiuoro-l1fi-hydroxy-20,B -butyryloxy-3oxo-16m methyl-1,4-pregnadien-21-oic acid.

59. A compound of Claim 1, 6a-fluoro-11/8,20;3-dihydroXy-3-oxo-16a-methyl-1,4-pregnadien-2l-oic acid.

6 0. A compound of Claim 1,, oa-fluoro-llfl-hydroxy- 20/3,2l-isopropylidenedioxy-l6a-methyl-l,4 pregnadien- 3,21-dione.

61. A compound of Claim 1, 6a-fluoro-11 8-hydroxy- 20a,2l-isopropylidenedioxy-l6a-methyl-1,4-pregnadiene- 3,21-dione.

62. A compound of Claim 1, 9oc-flIJOIO-1113-hYdIOXY- 20,8 ,21isopropylidenedioxy 16a methyl-1,4-pregnadiene-3,21-dione.

63. A compound of Claim 1, 9a-fluoro-11/3-hydroxy- 20u ,21isopropylidenedioxy 16a methyl-1,4-pregnadiene-3,21-dione.

64. A compound of Claim 1, methyl ester of 9a-fluoro- 11 3 hydroxy-20u-butyryloxy 3 oxo-16a-methyl-1,4- pregnadien-Zl-oic acid.

65. A compound of Claim 1, methyl ester of 9oc-flll0t0- 11 8 hydroXy-20B-butyryloxy 3 oxo16a-methyl-1,4- pregnadien-Zl-oic acid.

66. A compound of Claim 1, butyl ester of 6a-fluoro- 11 3d,20-dihydroxy-3-oxo 16oz methyl-4-pregnen-21-oic acl 67. A compound ofClaim 1, butyl ester of Got-fluoro- 1lfl,20,B -dihydroxy-3-oxo 16amethy1-4-pregnen-21-oic acid.

68. A compound of Claim 1, 6oc-fl11OIO-11fi,20a-dihydroxy-3-oxo-16a-methyl-l,4-pregnadien-21-oic acid.

69. A compound of Claim 1, butyl ester of 1113,2011dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid.

70. A compound of Claim 1, butyl ester of 115,205dihydroxy-3-oxo-16a-methyl-1,4-pregnadien-21-oic acid.

71. A compound of Claim 1, 2-hydroxyethyl ester of 6a fluoro-11fi,20B-dihydroxy 3 oxo-16a-methyl-1,4- pregnadien-ZI-oic acid.

72. A compound of Claim 1, benzyl ester of Goa-fluoro- 11 3,20 9dihydroxy-3-oxo 16oz methyl-1,4-pregnadien- 21-0ic acid.

73. A process for making a compound of the formula COORs wherein thegroup OR is in the oc or ,B -position; X is hydrogen, halogen or methyl;Y is hydrogen or halogen; Z is hydrogen or halogen having an atomicweight no greater than Y; R is hydrogen or methyl; R is hydrogen or acylas defined hereinafter and R is hydrogen, an alkali-metal, or asaturated hydrocarbon of 1-18 carbon atoms which is unsubstituted orsubstituted, or a corresponding unsaturated hydrocarbon, or collectivelyR and R are dialkylmethylene or cycloalkylidene, at least one of R R andR is other than a hydrogen atom; and A-B is which comprises (a) reactinga 21-hydroxy steroid of the general Formula II CHgOH wherein --AB-, X,Y, Z and R have the values given above, with an alcohol in the presenceof a copper (II) salt; or

(b) rearranging a compound of the general Formula III wherein --AB, X,Y, Z and R have the values given above, and Q is one of the groupings:

wherein R is an alkyl group and R is an acyl group, by treatment withstrong bases; and optionally thereafter, saponifying any ester groups ofthe thus-produced product, and/or esterifying a free ZO-hydroxy groupand/or condensing a 21-oic acid with a ketone.

References Cited UNITED STATES PATENTS 3,705,150 12/1972 Tuba et a1260239.5

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

